tbuckley/cabot-search huggingface dataset:
Abstract 6561: Specific binding mode of RNA binding protetin FAM120A to lncRNA
Authors: Kenichiro Kawai
Journal: Cancer Research (2023)

Abstract Long noncoding RNAs (lncRNAs) are defined as transcripts &amp;gt;200 nucleotides in length with no protein-coding potential. LncRNAs play diverse roles in regulating gene transcription, post-transcription, translation, and epigenetic modification through interaction with RNA binding proteins (RBPs). Here, we analyzed binding motif of a RBP, family with sequence similarity 120A (FAM120A), which is highly expressed in multiple cancer types and associated with poor prognosis. To investigate FAM120A interacting RNAs genome-wide, we conducted cross-linking immunoprecipitation combined with deep sequencing (CLIP-seq) using an anti-FAM120A antibody in osteosarcoma cell line, U2OS. We identified 37,151 FAM120A-binding clusters by a peak detection algorithm. Up to 92% of these clusters were found within about 5,700 mRNAs, with the highest enrichment at 3'-UTRs. Interestingly, other clusters located within 959 lncRNAs, with peaks at 5’ and 3’ end. Fold enrichment analysis of CLIP reads in comparison with input reads revealed that FAM120A binds more preferentially to lncRNA than mRNA (median fold enrichments, 4.81 (lncRNA) versus 4.41 (mRNA), P&amp;lt;0.001, Mann-Whitney U test). Motif analysis using the HOMER algorithm showed that FAM120A enriched sequence motifs in 3’ of mRNAs, 5’ and 3’ of lncRNAs were completely distinct. These results suggest that FAM120A may exhibit a motif-dependent selective binding to lncRNA in cancer cells. Given that RBPs bind to RNA molecules immediately after their transcription on chromatin, FAM120A may also selectively recognize RNA species and classify lncRNA and mRNA at the transcriptional stage. Since lncRNAs play pivotal roles in cancers FAM120A may exert oncogenic effects by the post-transcriptional regulation of a certain set of lncRNAs. Citation Format: Kenichiro Kawai. Specific binding mode of RNA binding protetin FAM120A to lncRNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6561.
Abstract 2689: Targeting the proteasome pathway in dactinomycin resistant Wilms tumors
Authors: Patricia Denise Ballesteros Tiburcio, Kenneth S. Chen
Journal: Cancer Research (2023)

Abstract Nephroblastomas or Wilms tumors are the most common pediatric renal cancer. Across all cases, the 5-year overall survival is over 90%. This is largely in part due to brute-force, chemotherapy regimens such as dactinomycin (actD) that have been routinely used to treat Wilms tumors. However, those that do respond to treatment still face a 15% chance of relapse. Patients with anaplastic tumor histology require more toxic therapies, and yet they still face a worse prognosis of only 66% 4-year survival and relapse rate of 43%. Furthermore, recurrence cuts survival rate down to 50%. With the widespread use of actD in Wilms tumors and other childhood malignancies, understanding the mechanism to recalcitrance against this chemotherapy can potentially reveal important vulnerabilities that can be exploited in the clinic. While transcriptomic and genomic analyses have been done in Wilms tumors, no targetable pathways have been identified in actD chemotherapy-resistant and anaplastic tumor cases. To that end, we performed ribosome sequencing of actD-treated anaplastic Wilms tumor cell line WiT49 and uncovered that the proteasome pathway is preferentially translated. Moreover, loss of proteasome subunits in a CRISPR library dropout screen sensitized the cells to actD. Consistent with these findings we found upregulation of proteasome subunit levels and proteasome enzymatic activity in Wilms tumor lines following actD treatment. To interrogate the effect of cotreating bortezomib with dactinomycin in vivo, we subcutaneously implanted anaplastic Wilms tumor patient-derived xenograft (PDX) lines in NOD/SCID Gamma (NSG) mice. Combinatorial treatment was found to be retard tumor growth compared to vehicle and single drug conditions. With further investigation, our findings can provide a foundation for exploring proteasome inhibitors with dactinomycin in clinical trials. Our study has important implications to improving the outcomes for not just for recurrent and anaplastic Wilms tumors, but to other pediatric cancers that use actD as well. Citation Format: Patricia Denise Ballesteros Tiburcio, Kenneth S. Chen. Targeting the proteasome pathway in dactinomycin resistant Wilms tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2689.
Abstract 45: Elephant p53 protects mice from carcinogen induced death
Authors: Lisa M. Abegglen, Jared S. Fowles, Aidan J. Preston, Aaron Rogers, Niraja Bhachech, Brayden B. Barney, Ryan Kennington, David H. Lum, Gareth Mitchell, Joshua D. Schiffman
Journal: Cancer Research (2023)

Abstract Elephants naturally have low rates of cancer, potentially due to evolved genetic changes in tumor suppressor elephant TP53 (EP53) and amplification of 19 TP53 retrogenes. A better understanding of the mechanisms of cancer suppression in elephants by EP53 and its retrogenes could lead to more effective human cancer therapeutics. EP53 induces a strong apoptotic response compared to human TP53, especially when combined with EP53-RETROGENE 9 (EP53-R9). EP53-R9 encodes a truncated p53 protein that induces apoptosis of human cancer cells independent of EP53 through a transcription-independent mechanism. To characterize EP53 and EP53-R9’s role in cancer suppression, transgenic mice were generated to replace mouse TRP53 with EP53. Additionally, a tetracycline inducible EP53-R9 gene was inserted into a safe harbor locus in mice. Carcinogenesis studies with 3-Methylcholanthene injection revealed that EP53 mice survived significantly longer compared to heterozygous or homozygousTRP53 mice (p &amp;lt;0.0001, 0.0102). Experiments to assess the protective role of EP53-R9 alone and combined with EP53 are ongoing. Several mouse embryonic fibroblast (MEF) cell lines were generated from these transgenic mice with 14 distinct genotypes with different combinations of TRP53, EP53, and EP53-R9. p53 target gene expression studies showed that MEFs with EP53 induce higher expression of MDM2 and p21 compared to TRP53-containing MEFs, suggesting that the cancer-protective effect observed in EP53 mice is due, in part, to greater activation of p53 signaling. These results support the need for future work to assess the potential of EP53-based therapeutics for human cancer. Citation Format: Lisa M. Abegglen, Jared S. Fowles, Aidan J. Preston, Aaron Rogers, Niraja Bhachech, Brayden B. Barney, Ryan Kennington, David H. Lum, Gareth Mitchell, Joshua D. Schiffman. Elephant p53 protects mice from carcinogen induced death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 45.
Abstract 5652: IL-19 blockade reprograms glioblastoma immunosuppressive microenvironment and overcomes chemo-resistance as revealed by single-cell transcriptome analyses
Authors: Gilbert A. Lee, Cheng-Yu Chen
Journal: Cancer Research (2023)

Abstract Glioblastoma multiforme (GBM) is the most aggressive brain tumor with chemo-resistant, immunosuppressive, and invasive property. Despite the application of standard therapies which include a combination of surgery, radiotherapy, and temozolomide (TMZ) chemotherapy, tumor inevitably recurred (in patients) at peritumoral region. Targeting multiple arms of the GBM-mediated immunosuppressive ability and their invasiveness can improve therapeutic efficacy. Genomic screening identified that IL-19 is a predicted immune suppressive cytokine in peritumoral region and was associated with poor survival in patients with GBM. IL-19 blockade inhibited both TMZ-sensitive and resistant tumor progression. Molecular studies revealed that silencing IL-19 markedly abrogated IL-19-WISP1-AKT signaling to inhibit TMZ-resistant GBM cell invasion, as well as weaken its suppressive ability on CD8+T cell activation. Single cell transcriptome analysis revealed that IL-19 blockade promoted T cell activation, upregulated effector function of T cell subsets, and reprogrammed tumor-associated macrophage subsets toward a weakened pro-tumoral phenotypes. Thus, Targeting IL-19 can be a novel therapeutic strategy to reverse immunosuppressive microenvironment and restrict invasiveness of chemo-resistant GBM. Citation Format: Gilbert A. Lee, Cheng-Yu Chen. IL-19 blockade reprograms glioblastoma immunosuppressive microenvironment and overcomes chemo-resistance as revealed by single-cell transcriptome analyses. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5652.
Abstract 6669: Antigen features are associated with response and survival after neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer
Authors: Wolfgang Beckabir, Steven Vensko, Alec Wilkinson, Gatphan Atassi, Mi Zhou, Kenneth Fowler, Leah Flick, Hsing-Hui Wang, Mark Woodcock, Karen McKinnon, Jonathan Serody, Tracy Rose, Matthew Milowsky, William Kim, Benjamin Vincent
Journal: Cancer Research (2023)

Abstract In the Phase II LCCC1520 trial, neoadjuvant chemo-immunotherapy (pembrolizumab with gemcitabine plus cisplatin) induced response in 22 of 39 muscle-invasive bladder cancer patients[1]. In this correlative analysis, we identify molecular features associated with response and survival. Associations of molecular subtype, TMB, and antigen presentation and immune checkpoint gene expression with response and survival were evaluated pre-and post-treatment. Neoantigens were predicted in 4 immuno-oncology data sets (LCCC1520, IMvigor210 cohorts 1[2] and 2[3], and Hugo[4]) using Landscape of Effective Neoantigens Software[5]. Effective neoantigen count (ENC) was calculated by binning predicted neoantigens by expression, binding affinity, binding stability, and tumor PD-1 and PD-L1 expression, then identifying the bin in which neoantigen count was most strongly associated with response in the discovery set. Using elastic net modeling with 10-fold cross-validation, survival was predicted from immune gene signature expression, clinical variables, TMB and ENC. Response was associated with pre-treatment molecular subtype and immune checkpoint expression. Pre-treatment ENC was associated with response in Hugo (discovery set, p = 0.020) and the three validation sets (p = 0.011, 0.042, 0.049). The final elastic net model (Cox P-H p = 5.6e-5) predicted survival significantly better than TMB (p = 0.055) or ENC (p = 0.141) alone. Post-treatment antigen presentation gene expression was associated with survival among non-responders. We identify pre-and post-treatment features associated with response and survival in the LCCC1520 trial and propose that tumor antigen presentation is a major driver of neoadjuvant chemo-immunotherapy outcomes. [1] Rose JCO 2022 [2] Balar Lancet 2017 [3] Mariathasan Nature 2018 [4] Hugo Cell 2016 [5] Vensko bioRxiv 2022 Citation Format: Wolfgang Beckabir, Steven Vensko, Alec Wilkinson, Gatphan Atassi, Mi Zhou, Kenneth Fowler, Leah Flick, Hsing-Hui Wang, Mark Woodcock, Karen McKinnon, Jonathan Serody, Tracy Rose, Matthew Milowsky, William Kim, Benjamin Vincent. Antigen features are associated with response and survival after neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6669.
Abstract 558: EGFR inhibition in lung adenocarcinoma upregulates cell surface expression of the placental antigen ALPP and enhances efficacy of ALPP-ADC therapy
Authors: Yihui Chen, Monica Hong, Hanwen Xu, Jody Vykoukal, Soyoung Park, Yining Cai, Ricardo A. León-Letelier, Fu Chung Hsiao, jennifer B. Dennison, Edwin J. Ostrin, Johannes F. Fahrmann, Hiroyuki Katayama, Samir M. Hanash
Journal: Cancer Research (2023)

Abstract Expression levels of placental alkaline phosphatase (ALPP) and ALPP-like 2 (ALPPL2) are relatively low in most cancer types, limiting potential benefits from ALPP or ALPPL2 targeting therapies. Enhancing their expression would be an attractive approach for targeted therapy. We have undertaken analysis of ALPP and ALPPL2 protein expression in whole cell extracts (WCE) and the surfaceome of 158 cancer cell lines and found ALPP, and to a less extent ALPPL2, to be expressed on the surface at relatively low levels across multiple cancer types. We explored various means to enhance ALPP expression in lung adenocarcinoma (LUAD) and found that induction of cancer cell quiescence via nutrient deprivation, or treatment with EGFR inhibitors, greatly enhanced ALPP surface expression. Mechanistic studies revealed that enhancement of surface ALPP expression in LUAD cells following gefitinib treatment was mediated through repression of MEK/ERK signaling and activation of the transcription factor FoxO3a, which was identified as an upstream transcriptional regulator of ALPP. Using xenograft models of LUAD, we further demonstrated that gefitinib treatment upregulates surface expression of ALPP in LUAD cells but not in normal tissues. Combination therapy with gefitinib and an ALPP antibody conjugated with Monomethylauristatin F resulted in enhanced tumor suppression compared with gefitinib alone. Our findings support a novel combination treatment modality that boosts the efficacy of ALPP-ADC directed therapy. Citation Format: Yihui Chen, Monica Hong, Hanwen Xu, Jody Vykoukal, Soyoung Park, Yining Cai, Ricardo A. León-Letelier, Fu Chung Hsiao, jennifer B. Dennison, Edwin J. Ostrin, Johannes F. Fahrmann, Hiroyuki Katayama, Samir M. Hanash. EGFR inhibition in lung adenocarcinoma upregulates cell surface expression of the placental antigen ALPP and enhances efficacy of ALPP-ADC therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 558.
Abstract 6591: A universal atlas of cellular and oncogenic phenotypes
Authors: Corey Weistuch, Kevin Murgas, Ken Dill, Larry Norton, Joseph Deasy, Allen Tannenbaum
Journal: Cancer Research (2023)

Abstract Tumors and healthy tissues exhibit gene expression variability in many of the same pathways. We propose that these commonalities result from a performance trade-off between universal cellular phenotypes; each phenotype is defined by an orthogonal gene expression profile identified using unsupervised dimensionality reduction. Using two publicly available RNA-seq datasets (n=54 normal tissues; n=1504 cancer cell lines), we show that both healthy and cancerous cells occupy a trade-off between five canonical phenotypes: OxPhos, Warburg, Fibroblastic, Immune, and Growth. Each cell is assigned a phenotype score that, as we demonstrate, predicts differential drug sensitivities and mutational signatures, even among cancers of the same tissue type. Since these phenotype scores are defined using only healthy tissues, they can be generally applied to other diseases as well. Citation Format: Corey Weistuch, Kevin Murgas, Ken Dill, Larry Norton, Joseph Deasy, Allen Tannenbaum. A universal atlas of cellular and oncogenic phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6591.
Abstract 5872: Spatial immunophenotypes contribute to predict survival of triple-negative breast cancer assessed as Miller-Payne grade 4 and N0 after neoadjuvant therapy
Authors: Jianli Ma, Yuwei Deng, Dawei Chen, Xiaomei Li, Zhiyong Yu, Haibo Wang, Lei Zhong, Yingjie Li, Chengqin Wang, Xiaoping Zhou, Xiang Li, Qingyuan Zhang, Jinming Yu
Journal: Cancer Research (2023)

Abstract Objectives Some Miller-Payne 4 and N0 patients with triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) who had better survival should avoid treatment escalation. We aimed to identify these patients based on spatial distributions of immunophenotypes at initial diagnosis. Methods We retrospectively analyzed 272 TNBC patients with Miller-Payne grade 4/5 and N0 for tumor-infiltrating lymphocytes (TILs) in relation to clinical survival. The spatial immunophenotypes were analyzed by multiplexed ion beam imaging by time of flight combined with proteomic. A prognostic classifier was established by the random forest algorithm. Results The 5-year disease-free survival (DFS) was 63.8% for Miller-Payne 4 and 83.0% for Miller-Payne 5 (p=0.003), and overall survival (OS) was 71.0% and 85.5% respectively (p=0.007). High TILs were significantly associated with better DFS and OS in the Miller-Payne 4 patients (both p=0.016). Spatially, Miller-Payne 4 with good prognosis exhibited inflamed phenotype, with dominant CD8+ T cells on tumor center, few scattered CD68+ myeloid-derived cells far away from T cells, and deposit of increased lymphocyte activate molecules. Miller-Payne 4 with poor prognosis presented excluded phenotype, with few CD8+ T cells restricted to invasive margin, high density of CD14+CD68+CD11c+ myeloid cells with related molecules. These spatial immunophenotypes provided a good classifier model (AUC=0.975) to identify Miller-Payne 4 patients with different prognosis. We also observed similar signatures in Miller-Payne 5. Conclusion Spatial immunophenotypes may indicate the prognosis in TNBC assessed as Miller-Payne 4 and N0. Citation Format: Jianli Ma, Yuwei Deng, Dawei Chen, Xiaomei Li, Zhiyong Yu, Haibo Wang, Lei Zhong, Yingjie Li, Chengqin Wang, Xiaoping Zhou, Xiang Li, Qingyuan Zhang, Jinming Yu. Spatial immunophenotypes contribute to predict survival of triple-negative breast cancer assessed as Miller-Payne grade 4 and N0 after neoadjuvant therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5872.
Abstract 1946: Development and application of genetic ancestry reconstruction methods to study diversity of patient-derived models in the NCI PDXNet Consortium
Authors: Brian J. Sanderson, Paul Lott, Katherine Chiu, Juanita Elizabeth Quino, April Pangia Vang, Michael W. Lloyd, PDXNet Consortium, Anuj Srivastava, Jeffrey H. Chuang, Luis G. Carvajal-Carmona
Journal: Cancer Research (2023)

Abstract Personalized medicine holds great promise for improving cancer outcomes, yet there is a large inequity in the demographics of patients from whom genomic data and models, including patient derived xenografts (PDX), are developed and for whom treatments are optimized. In this study we develop a genetic ancestry pipeline for the Cancer Genomics Cloud, which we use to assess the diversity of models currently available in the National Cancer Institute (NCI) supported PDX Development and Trial Centers Research Network (PDXNet). We show that there is an over-representation of models derived from patients of European ancestry, which is consistent with other cancer model resources. We discuss these findings in the context of disparities in cancer incidence and outcomes among demographic groups in the US. For example, for the top cancer health disparities affecting African Americans and Latinos, there is a significant lack of ethnic/race appropriate models needed to advance pre-clinical research and personalized clinical treatment. For stomach and liver tumors, which represent disparities in these two minority populations, there are only three available models derived from patients from such backgrounds. Fortunately, ongoing NCI-funded efforts in minority focused PDXNet centers are actively addressing these gaps. We further discuss these results in the context of power analyses to highlight the immediate need for the development of models from minority populations to address cancer health equity in personalized medicine. Citation Format: Brian J. Sanderson, Paul Lott, Katherine Chiu, Juanita Elizabeth Quino, April Pangia Vang, Michael W. Lloyd, PDXNet Consortium, Anuj Srivastava, Jeffrey H. Chuang, Luis G. Carvajal-Carmona. Development and application of genetic ancestry reconstruction methods to study diversity of patient-derived models in the NCI PDXNet Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1946.
Abstract 4630: Deep Immuno-profiling of syngeneic tumor mouse models for preclinical studies
Authors: Anais Joachim, Emilie Maturin, Marielle Mello, Lillia Hadjem, Magali Grange, Olivier Deas, Ana Zarubica, Bernard Malissen, Hervé Luche
Journal: Cancer Research (2023)

Abstract Identification of major cellular players involved in progression of cancer is key to success of new immunotherapies. It is however a daunting challenge due to the complex interplay between tumor cells and the immune system. Component of innate and adaptive immunity may be directed to a pro- or anti-tumor function. In order to cope with the complexity of the tumor microenvironment (TME), it is necessary to use an experimental approach characterizing the heterogeneity of cell types, the evolution of their relative proportion and their fine-tuned functional specificity. This approach should lead to the identification of new cellular biomarkers characteristics of different stages of tumor cancer progression. To decipher the impact of immunotherapy treatments, cellular phenotyping of leukocytes infiltrating TME but also those present in peripheral organs is necessary. In order to increase our understanding in the precise mode of action of anti-PD1 treatment at the cellular level in sensitive and unsensitive syngeneic models, we investigated immunophenotypes and responses to immune checkpoint inhibitor (ICI) of several hallmark tumor models (MC38, CT26, B16F10, B16-OVA, RENCA, EMT6) in immunocompetent mouse models by flow and mass cytometry. We compared growth kinetics and profiled the immune cell composition of tumor microenvironment (TME), draining lymph node (dLN) and blood in order to establish immune-phenotypic cell signatures that correlates with treatment efficacy. Supervised, unsupervised and integrative data analysis arewere used to identify significant changes across different experimental settings. Our results indicate that each model possesses a unique tumor-immune infiltrate profile that can be modulated with immunotherapies. Overall, these studies provide an important resource of highly well-characterized syngeneic tumor model and highlight the importance of tumor immune landscape changes across models that will drive selection of the most appropriate model to test novel immunotherapeutic agents and enhance our translation of knowledge from syngeneic models to human tumors. Citation Format: Anais Joachim, Emilie Maturin, Marielle Mello, Lillia Hadjem, Magali Grange, Olivier Deas, Ana Zarubica, Bernard Malissen, Hervé Luche. Deep Immuno-profiling of syngeneic tumor mouse models for preclinical studies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4630.